1. Field of the Invention
This invention relates to methods of preparing matrix metalloprotease inhibitors, particularly 3-arylsulfur hydroxamic acids.
2. Background Information
I. MMP Inhibitors
Matrix metalloproteases (xe2x80x9cMMPsxe2x80x9d) are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone resorptive diseases (such as osteoporosis), chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes.
Furthermore, inhibitors of MMP also are known to substantially inhibit the release of tumor necrosis factor (TNF) from cells and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease.
MMP inhibition is, therefore, recognized as a good target for therapeutic intervention. Consequently, inhibitors of MMPs provide useful treatments for diseases associated with the excessive degradation of extracellular matrix and diseases mediated via TNF and several MMP inhibitors are currently being developed for such uses.
One particular class of MMP inhibitors are the 3-arylsulfur hydroxamic acids described in EP 0 780 386 A1, published Jun. 25, 1997. This publication discloses MMP inhibitors of Formula I,
Yxe2x80x94C(xe2x95x90O)xe2x80x94C(R1)(R2)xe2x80x94CH2xe2x80x94S(O)nR3 
where n, Y, R1, R2 and R3 are as described below in the Summary of the Invention.
WO 97/24117, published Jul. 10, 1997, discloses 3-aryl sulfur hydroxamic acids of formula, HON(H)xe2x80x94C(xe2x95x90O)xe2x80x94Cp(R1)(R2)xe2x80x94C(R3)(R4)xe2x80x94S(O)nxe2x80x94Cm(R5)(R6)xe2x80x94Ar, where p, m, n and R1, R2, R3, R4, R5, R6 and Ar are as described in WO 97/24117.
WO 98/05635, published Feb. 12, 1998, discloses 3-arylsulfur hydroxamic acids of formula Bxe2x80x94S(O)0-2xe2x80x94CHR1xe2x80x94CH2xe2x80x94COxe2x80x94NHOH, where B and R1 are as described in in WO 98/05635.
WO 98/13340, published Apr. 2, 1998, discloses xcex2-sulfonyl hydroxamic acids of HONHC(xe2x95x90O)xe2x80x94CHR2xe2x80x94CH2xe2x80x94S(O)2R1 where R1 and R2 are as described therein.
However, the processes disclosed in these publications for preparing 3-arylsulfur hydroxamic acids proceed via the nucleophilic attack of a thiol on the xcex2-carbon of a carboxylate derivative, either displacing a leaving group at the xcex2-carbon or performing a Michael reaction on an xcex1,xcex2 unsaturated ester or acid. Thus, the disclosed processes are limited by the availability of the corresponding thiols and the xcex2-substituted carboxylate derivatives and xcex1,xcex2 unsaturated esters. This invention provides novel processes and novel intermediates that are not dependent on the availability of the reagents used in the above publications.
The use of 3-arylsulfonyl hydroxamic acids as MMP inhibitors is also described in WO 97/49679 A1, published Dec. 31, 1997.
II. Preparation of Aryl Alkyl Sulfides
Aryl haloalkyl sulfides are valuable intermediates in synthetic organic processes and they are commonly made by free radical halogenation of a precursor aryl alkyl sulfide. The aryl alkyl sulfide is in turn typically available via sulfonation of a precursor aryl hydrocarbon, reduction to an aryl thiol and alkylation of the thiol. It would be useful to have methods of directly converting arylsulfonyl derivatives to aryl methyl sulfides.
There have been various reports of the reactions between trialkyl phosphites and aryl sulfonyl derivatives. See, for example, R. W. Hoffman, T. R. Moore and B. J. Kagan, (xe2x80x9cThe Reaction between Triethyl Phosphite and and Alkyl and Aryl Sulfonyl Chloridesxe2x80x9d) J. Am. Chem. Soc., 78:6413-6414 (1956); J. M. Klunder and K. Barry Sharpless, (xe2x80x9cA Convenient Synthesis of Sulfinate Esters from Sulfonyl Chloridesxe2x80x9d) J. Org. Chem., 52:2598-2602 (1987); and J. Cadogan (xe2x80x9cOxidation of Tervalent Organic Compounds of Phosphorousxe2x80x9d) Quarterly Reviews, 16:208-239 (1962). The reaction of benzensulfenyl chloride with triethylphosphite to yield ethyl phenyl sulfide has also been reported, T. Mukaiyama and H. Ueki, (xe2x80x9cThe Reactions of Sulfur-containing Phosphonium Saltsxe2x80x9d) Tetr. Lett., 35:5429-5431 (1967). Aryl sulfonyl chlorides have also been converted to aryl methyl sulfides in three steps by treatment of an aryl sulfonyl chloride with lithium diphenylphosphide, Ph2PLi, to afford a P-diphenyl-aryl sulfophosphamide followed by cathodic reduction and methylation of the resulting aryl thiolate, J. Pilard and J. Simonet. (xe2x80x9cThe Cathodic Cleavage of the S-P Bond. Synthesis and Electrochemical Behaviour of Sulfonamide Phosphorous Analoguesxe2x80x9d), Tetr. Lett., 38(21):3735-3738 (1997).
In one aspect, this invention provides processes for the preparation of a compound of Formula I:
Yxe2x80x94C(xe2x95x90O)xe2x80x94C(R1)(R2)xe2x80x94CH2xe2x80x94S(O)nR3 
Formula I 
wherein:
Y is hydroxy or XONXxe2x80x94, where each X is independently hydrogen, lower alkyl or lower acyl;
R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group;
R3 is aryl; and
n is 0, 1 or 2;
comprising the steps of:
(1) alkylating a compound of Formula II,
ROxe2x80x94C(xe2x95x90O)xe2x80x94CH(R1)(R2) 
Formula II 
where R is alkyl or hydrogen, with an arylmethylthio derivative of Formula III, ArSCH2xe2x80x94Z, wherein Ar is an aryl group and Z is a leaving group, to provide a compound of Formula IV,
ROxe2x80x94C(xe2x95x90O)xe2x80x94C(R1)(R2)xe2x80x94CH2SAr, and 
Formula IV 
(2) converting the compound of Formula IV to a compound of Formula I by replacing the group ROxe2x80x94 with XONHxe2x80x94 and optionally oxidizing the ArS group as necessary in either order.
The invention also provides novel aryl haloalkyl sulfide and aryl alkyl sulfide intermediates useful for the preparation of compounds of Formula I and novel methods of preparing aryl alkyl sulfides.
Definitions
As used herein, the term xe2x80x9c(Crp-q) alkylxe2x80x9d means a linear or branched fully-saturated hydrocarbon radical having p to q carbon atoms; for example, a xe2x80x9cC1-4 alkylxe2x80x9d means a linear or branched fully saturated hydrocarbon radical having one to four carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.
Unless otherwise specified, the term xe2x80x9clower alkylxe2x80x9d means a C1-4 alkyl radical.
As used herein, the term xe2x80x9c(C3-6) cycloalkylxe2x80x9d means a fully saturated cyclic hydrocarbon radical of three to six ring carbon atoms, e.g., cyclopropyl, cyclopentyl and the like.
As used herein, the term xe2x80x9clower acylxe2x80x9d refers to a group xe2x80x94C(xe2x95x90O)R, where R is a (C1-4)alkyl radical.
As used herein, the term xe2x80x9cloweralkoxyxe2x80x9d refers to a group xe2x80x94OR, where R is a (C1-4)alkyl radical.
As used herein, the term xe2x80x9c(C7-10)alkoxyxe2x80x9d refers to a group OR, where R is a (C7-10)alkyl radical.
As used herein, the term xe2x80x9carylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, optionally substituted phenyl, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, xe2x80x94COOR (where R is hydrogen or alkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
As used herein, the term xe2x80x9carylenexe2x80x9d means a divalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, optionally substituted phenyl, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, xe2x80x94COOR (where R is hydrogen or alkyl). More specifically the term aryl includes, but is not limited to, 1,4-phenylene and 1,2 phenylene.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHeterocycloxe2x80x9d means a saturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. The heterocyclo ring may be optionally fused to a benzene ring or it may be optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, halo, cyano, acyl, monosubstituted amino, disubstituted amino, carboxy, or alkoxycarbonyl. More specifically the term heterocyclo includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and the derivatives thereof.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkanesulfonyloxy, arenesulfonyloxy, amino, alkylcarbonyloxy, arylcarbonyloxy, such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, N,Oxe2x80x94 dimethylhydroxylamino, acetoxy, and the like.
In one aspect, this invention provides a process for the preparation of a compound of Formula I:
Yxe2x80x94C(xe2x95x90O)xe2x80x94C(R1)(R2)xe2x80x94CH2xe2x80x94S(O)nR3 
Formula I 
wherein:
Y is hydroxy or XONX, where each X is independently hydrogen, lower alkyl or lower acyl;
R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group;
R3 is aryl; and
n is , 1 or 2;
comprising the steps of:
(1) alkylating a compound of Formula II,
ROxe2x80x94C(xe2x95x90O)xe2x80x94CH(R1)(R2) 
Formula II 
where R is alkyl or hydrogen, with an arylmethylthio derivative of Formula III, ArSCH2xe2x80x94Z, wherein Ar is an aryl group and Z is a leaving group, to provide a compound of Formula IV,
ROxe2x80x94C(xe2x95x90O)xe2x80x94C(R1)(R2)xe2x80x94CH2SAr and 
Formula IV 
(2) converting the compound of Formula IV to a compound of Formula I by replacing the group ROxe2x80x94 with XONHxe2x80x94 and optionally oxidizing the ArS group as necessary in either order.
Unlike the methods disclosed in EP 0 780 386 A1, published Jun. 25, 1997, WO 97/24117, published Jul. 10, 1997, WO 98/05635, published Feb. 12, 1998 and WO 98/13340, published Apr. 2, 1998, for the synthesis of 3-arylsulfur hydroxamic acids, the processes of the present invention proceed via the alkylation of the xcex1-carbon of a carbonyl group with a halomethyl aryl sulfide. The invention also provides novel halomethyl aryl sulfides, such as chlorophenoxyphenyl chloromethyl sulfide and methods for their preparation. Thereby, the inventors are able to prepare compounds of Formula I by novel processes not previously available.
These reaction processes are shown in Scheme A, below. 
Compounds of Formula IV may be converted to compounds of Formula I by conversion of the carboxyl group to a group xe2x80x94C(xe2x95x90O)xe2x80x94L where L is a leaving group under nucleophilic displacement conditions followed by displacement of L with hydroxylamine (or an alkylated derivative). The resulting hydroxamic acid is then oxidized as necessary to give the desired sulfoxide or sulfone. Oxidation to the sulfoxide is accomplished by treatment with mild oxidizing agents such as sodium or potassium metaperiodate or one equivalent potassium peroxymonosulfate (Oxone(trademark)). Other oxidants that may be used include peracids, (e.g. performic or peracetic acid) or sodium perborate/organic acid mixtures (e.g. performic or peracetic acid). The reaction may be halted at the sulfoxide stage by limiting the quantity of reagents, temperature and reaction time. Further oxidation to the sulfone is accomplished by treatment under more vigorous conditions with organic peracids such as m-chloroperbenzoic acid or two equivalents of sodium peroxymonosulfate. Alternatively, other oxidizing agents such as perborates, e.g., sodium perborate, in a carboxylic acid solvent such as formic, acetic or propionic acid may be used. These last two steps may also be reversed, i.e., oxidation of the sulfur moiety may precede conversion of the acid to the hydroxamate. However, overall yields are usually higher with the former sequence.
Compounds of Formula II, ROxe2x80x94C(xe2x95x90O)xe2x80x94CH(R1)(R2), can be purchased from commercial suppliers or are readily available by published procedures known to one of skill in the art. See, for example, EP 0 780 386 A1.
Compounds of Formula III, ArSCH2xe2x80x94Z, are made by oxidation of the precursor arylmethylthioether. Compounds ArSCH2Cl are made by oxidation with sulfuryl chloride in aprotic solvents such as methylene chloride, t-butylmethyl ether or hexane. The oxidation may be done at room temperature or at lower temperatures, e.g., from about 0-10xc2x0 C. Other reagents, such-as N-chlorosuccinimide, may also be used. Compounds ArSCH2Br are made by oxidation with sulfuryl bromide or other reagents such as N-bromosuccinimide.
Compounds of Formula III, ArSCH2xe2x80x94Z, where Z is chloro or bromo may also be made from the corresponding thiol as shown below: 
Arylmethylthioethers are generally available either from commercial vendors or published literature procedures. For example, they may be made by sulfonylating an aryl compound to the corresponding sulfonic acid, reducing the sulfonic acid to a thiol and methylating the thiol.
Alternatively, as shown in Scheme B, the inventors have unexpectedly discovered that arylsulfonyl halides can be converted directly to arylmethylthioethers in one step by treatment with trimethylphosphite. The conversion proceeds best if the trimethylphosphite treatment is followed by treatment with a base. Either an organic base such as an alkylamine (e.g. triethylamine) or a hydroxylic base such as an alkali metal hydroxide or an alkaline earth metal hydroxide may be used. However, the conversion may also be accomplished, albeit in somewhat lower yield, without the addition of a base. In such processes, the yield of the aryl methyl sulfide may be increased by heating to elevated temperatures, e.g., as high as about 100xc2x0 C., preferably as high as about 130xc2x0 C. (internal temperature). Consequently, the invention also provides a novel method of preparing aryl methyl sulfides by directly reducing/alkylating an arylsulfonyl halide with trimethyl phosphite. 
The method is particularly useful for forming compounds of formula ArSCH3, wherein Ar has the formula xe2x80x94Ar1xe2x80x94Axe2x80x94Ar2, where Ar1 and Ar2 are phenyl rings, each independently optionally substituted and A is a bond, CH2 or xe2x80x94Oxe2x80x94, and more particularly where, A is oxygen, Ar1 is phenyl and Ar2 is 4-chlorophenyl.
Subsequent halogenation of ArSCH3 then provides key intermediates of formula ArSCH2xe2x80x94X where X is halo. Useful key intermediates include those where Ar is xe2x80x94Ar1xe2x80x94Axe2x80x94Ar2, wherein Ar1 and Ar2 are independently optionally substituted phenyl, X is halo, A is oxygen, or CH2. A particularly useful intermediate is that wherein Ar1 is phenyl, Ar2 is halophenyl, and A is oxygen. useful intermediate is that wherein Ar1 is phenyl, Ar2 is halophenyl, and A is oxygen.
Alkylation of a compound of Formula II with a compound of Formula III may be accomplished by conditions known to one of skill in the art such as converting a compound of Formula II to an enolate or enol followed by reaction with a compound of Formula III. Other conditions include forming the dianion of the acid (i.e., compound of Formula II where Rxe2x95x90H) by treatment with two equivalents of a base such as lithium diisopropylamide or lithium hexamethyldisilazide and alkylating with one equivalent of a compound of Formula III.
In one embodiment, a compound of Formula II was converted to a silylketene acetal as shown in Reaction Scheme C (where Silyl represents a silyl group), followed by Mukaiyama coupling of the acetal with a compound of Formula III. The coupling is generally done in an anhydrous aprotic solvent such as a halocarbon or hydrocarbon (methylene chloride, chloroform, benzene, toluene etc.) in the presence of a Lewis acid such as zinc chloride, zinc bromide, zinc iodide, ferric bromide or titanium tetrachloride. Silylketene acetals may be readily prepared from compounds of Formula II by procedures such as those described in C. Ainsworth, F. Chen, Y. N. Kuo xe2x80x9cKetene Alkyltrialkylsilyl Acetals: Synthesis, Pyrolysis and NMR Studiesxe2x80x9d) J. Organometallic Chem., 46:59-87 (1972). A variety of silyl protecting groups, e.g., t-butyldimethylsilyl, trimethylsilyl, etc. may be used. Silylketene acetals can be formed from either the ester (Rxe2x95x90alkyl) or acids (Rxe2x95x90H) of Formula II. Formation of the silylketene acetal from the acid may be accomplished using two equivalents of base and quenching with two equivalents of the silylating, reagent. Subsequent alkylation with a compound of Formula III followed by a hydrolytic work up then directly yields a carboxylic acid of Formula IV. Reagents that may be used to form the silylketene acetal include trimethylysilyl triflate, trimethylsilyl chloride or bromide, tert-butyldimethylsilyl chloride and bis-trimethylsilyl acetamide. 
Alternatively, an enolate of a compound of Formula II may be directly alkylated with a compound of Formula III, thus avoiding the intermediacy of the silylketene acetal. The enolate is formed under standard conditions, by treatment with a non-nucleophilic organic base such as lithium diisopropylamide or lithium hexamethyldisilazide, or a metal hydride such potassium hydride, under anhydrous conditions, typically at room temperature, in a polar aprotic solvent such as tetrahydrofuran, dimethoxyethane or glyme and the like. Subsequent addition of a compound of a Formula III followed by heating if necessary to reflux temperatures, e.g., 60-80xc2x0 C., provides an alkylated product of Formula IV. The enolate may also be formed from the corresponding xcex1-bromoester of a compound of Formula II by treatment with zinc to form the zinc enolate which can then be alkylated.
Though the processes described herein may be used to prepare a variety of 3-arylsulfur hydroxamic acids and their corresponding carboxy and ester derivatives, they are particularly useful for preparing compounds of Formula I wherein the aryl group Ar is of the formula xe2x80x94Ar1xe2x80x94Axe2x80x94Ar2, wherein Ar1 and Ar2 are phenyl rings, each independently optionally substituted and A is a bond, xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94.
Other useful compounds that may be made by the methods of the invention include compounds of Formula I where R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group, particularly a tetrahydropyranyl group.
Additional useful hydroxamic acids that may be prepared include those that are xcex1, xcex1-disubstituted, i.e., neither R1 nor R2 are hydrogen.
Utility and Administration
As described earlier, the compounds made by these processes are MMP inhibitors, useful in treating a variety of diseases as disclosed in EP 0 780 386 A1, published Jun. 25, 1997; WO 97/24117, published Jul. 10, 1997; and WO 98/05635, published Feb. 12, 1998.
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Abbreviations used in the examples are defined as follows: xe2x80x9cDMFxe2x80x9d for dimethylformamide, xe2x80x9cNaOHxe2x80x9d for sodium hydroxide, xe2x80x9cDMSOxe2x80x9d for dimethylsulfoxide, xe2x80x9cPTLCxe2x80x9d for preparatory thin layer chromatography, xe2x80x9cEtOAcxe2x80x9d for ethyl acetate, xe2x80x9cLDAxe2x80x9d for lithium diisopropylamide and xe2x80x9cTMSClxe2x80x9d for trimethylsilylchloride.